Recent investigations into pathogenetic mechanisms in rheumatoid arthritis have provided evidence for the abnormal handling of infections with Epstein-Barr virus. Many patients with RA have a circulating antibody (RAP) that reacts with an antigen (RANA) found only in EB virus infected cells, and RANA has been found in rheumatoid synovial tissue. Studies from our laboratory have demonstrated that EB virus-induced lymphocyte proliferation occurs more rapidly in cells from patients with RA than in lymphocytes from healthy donors. In investigating the mechanisms for altered susceptibility to EBV infection in RA cells, we have found that the regulation of B cell proliferation normally provided by T cells does not occur in the RA cells. The studies proposed in this application are directed at delineating the nature of that cellular defect. We will prepare purified populations of T cells, B cells, and monocytes from RA patients and from normal individuals who have been matched for compatibility in mixed leukocyte cultures, and by combining them will determine which RA cell type functions abnormally. In addition, we will determine if serum factors in RA are responsible for producing the defective cellular regulation. Studies in families of patients with RA are planned to determine if the altered handling of EB virus is associated with genetic and/or environmental factors. We also plan to assess EB virus-induced outgrowth in lymphocytes from children with juvenile chronic polyarthritis to help determine whether defective cellular regulation is a primary event leading to the abnormal handling of EB virus on exposure, or if the cellular defect is secondary to prior exposure to the EB virus.